tbuckley/cabot-search huggingface dataset:
Abstract P3007: Exposure To Particulate Air Pollution Dysregulates Splenic Inflammation Resolution And Erythrocyte Processing
Authors: Haley Asplund, Petra Haberzettl, Jason Hellmann, Daniel J Conklin, Steven Jones, Aruni Bhatnagar, Brian E Sansbury
Journal: Circulation Research (2022)

Chronic exposure to ambient particulate matter (PM) increases the risk of cardiovascular disease (CVD). One proposed mechanism linking PM exposure and CVD is the induction of low-grade systemic inflammation that underlies disease progression. However, whether exposure to fine PM (PM 2.5 ) directly affects the endogenous pathways that resolve the inflammatory response is not known. Resolution of inflammation is distinct from anti-inflammation in that rather than blunting the magnitude of the initial inflammatory response, it is the active promotion and acceleration of its decay. Defective or insufficient resolution is a hallmark of many chronic inflammatory diseases including atherosclerosis and diabetes. Therefore, the overall goal of this study was to elucidate how PM exposure impacts the resolution of inflammation and how this relates to the subtle, but extensive pathological changes brought about by PM exposure. We found that in mice exposed PM 2.5 for 30 days there was a significant decrease in the abundance of specialized lipid mediators that promote resolution (SPMs) in the spleen. The changes in spleen are particularly critical due to its central role in regulating immune response dynamics and as a filter to remove senescent and damaged erythrocytes. While SPMs are known to enhance macrophage erythrophagocytosis ex vivo , how decreased in vivo abundance affects splenic function remains unclear. Therefore, we performed RNA sequencing of PM 2.5 -exposed spleens and found that numerous pathways involved in both erythrophagocytosis and myelopoiesis were significantly upregulated, including those related to myeloid cell homeostasis and development, erythrocyte differentiation, iron ion homeostasis, and heme biosynthesis and metabolism. Additionally, we identified significant alterations in circulating red blood cells, including decreased expression of CD47, a prominent marker of self and “don’t eat me signal”, on the surface of circulating erythrocytes after exposure to PM 2.5 , as well as increased red cell distribution width. Together, these data suggest that PM exposure alters red blood cells and may stimulate enhanced erythrophagocytosis in the spleen, increasing red blood cell turnover.
Abstract P3132: High-salt Diet Increases Blood Cholesterol: Potential Role Of Hepatic Enzyme CYP51
Authors: MyungYoon Kim, Asma Nawaz, Isabelle Pellot, Prediman K Shah, Eugenio Cingolani, Eduardo Marban, Jae Hyung Cho
Journal: Circulation Research (2022)

Introduction: The increased consumption of dietary fat has been well established to lead to cardiovascular disease via the elevation of lipids in serum. High blood pressure is also commonly associated with high serum cholesterol levels, but the relationships among blood pressure, dietary sodium intake and serum cholesterol have not been fully elucidated. Hypothesis: An increase in the intake of salt causes an elevation of serum cholesterol through the activation of hepatic enzymes critical to cholesterol synthesis. Methods: Dahl salt-sensitive rats (n=6) were fed a high-salt (HS) diet (8% NaCl) from 7 weeks of age to induce hypertension. Rats fed a normal-salt (NS) diet (0.3% NaCl; n=6) served as controls. Blood pressure was measured non-invasively using a tail artery cuff. Blood was withdrawn from 6-hour fasting HS and NS-fed rats to check serum cholesterol levels. Low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very-low density lipoprotein (VLDL) cholesterols were measured. Gene expression array and western blot were performed in liver protein extracts from HS and NS-fed rats. Results: Systolic blood pressure was elevated in HS-fed rats compared to NS-fed rats at 16 weeks of age (225±23 vs. 156±18 mmHg, p=0.0002). Serum fasting cholesterol was higher in hypertensive rats compared to normotensive rats (194±49 vs. 102±12 mg/dL, p=0.0013). LDL cholesterol was higher in HS-fed rats compared to NS-fed rats (83±9 vs. 60±10 mg/dL, p=0.0024), while HDL and VLDL cholesterol were not. Hepatic cholesterol synthesis gene array revealed significant up-regulation of 3 genes in hypertensive rats in comparison to normotensive rats ( Apoa1 fold change [FC] 2.84, p&lt;0.0001; Tm7sf2 FC 2.45, p=0.0004; Cyp51 FC 2.44, p=0.0002). Western blot of hepatic protein extracts showed a definitive increase in CYP51 in HS-fed rats compared to NS-fed rats (normalized against GAPDH, 2.7-fold increase, p=0.0018). Conclusions: A high-salt diet increased serum cholesterol levels, potentially via activation of liver enzyme CYP51, which is crucial for the synthesis of cholesterol in the liver. Further research is warranted to investigate the mechanisms of how high-salt diets can increase CYP51 in the liver.
Abstract P3118: Understanding And Overcoming Doxorubicin-Induced Cardiotoxicity Via Mitochondrial Antioxidants
Authors: Lindsey R Farris, Rama D Yammani, Leslie B Poole
Journal: Circulation Research (2022)

Chemotherapeutic-induced cardiomyopathies have surpassed cancer as the leading cause of death in patients post-remission. The highly efficacious anti-neoplastic agent, Doxorubicin (DOX), is a major culprit of dose-limiting cardiotoxicity, though the method of insult is not completely understood. While cardiotoxicity is likely multifaceted, a route of interest is the upregulation of reactive oxygen species (ROS) that leads to mitochondrial damage and other cellular complications within cardiomyocytes. Cardiomyocytes are heavily reliant on their mitochondria as the source of cellular energy, as 30% of cell volume is taken up by the organelle. To understand and counter ROS accumulation in the mitochondria with DOX administration, we are investigating the role of mitochondrially targeted antioxidants. We have found that DOX increases cytotoxicity and caspase-3 cleavage in cardiomyoblasts in vitro while inhibiting activation of nuclear factor erythroid 2-related factor 2 (Nrf2) which plays an important role in cellular antioxidant response. We have also found MitoQ, an analog of coenzyme Q, to be protective against DOX cytotoxicity in cell culture. To further evaluate MitoQ ability to mitigate DOX cardiotoxicity, we are investigating the mechanism of action via the Keap1/Nrf2 pathway, interplay with DOX anti-cancer efficacy, and in vivo therapeutic potential. The endogenous mitochondrial peroxiredoxin, Prx3, has been implicated as an important player in both tumor growth and ROS management in disease models, and it has been shown to be upregulated in the hearts of mice as well as in H9C2 cardiomyoblasts after DOX exposure. We aim to understand how the high ROS environment created by DOX-administration leads to potential post-translational modification of Prx3, thus affecting its role as a possible signaling protein. The interactions between MitoQ and Prx3 will also be elucidated. These in vitro studies will guide future in vivo experimentation to further understand DOX cardiotoxicity and evaluate a potential adjuvant therapeutic.
Abstract P3068: TNFR1 Regulates Cellular Proliferation And Not Pathogenicity Of Cd4 <sup>+</sup> T-lymphocytes During Ischemic Heart Failure
Authors: Vinay Kumar, Rachel Rosenzweig, Suman Asalla, Sarita Nehra, Sumanth D Prabhu, Shyam S Bansal
Journal: Circulation Research (2022)

Ischemic heart failure (HF) is associated with elevated inflammatory responses including pro-inflammatory cytokines, such as Tumor necrosis factor (TNF) α [and its cognate receptors, TNF receptor (TNFR) 1 and TNFR2] and pathological switching of CD4 + T-cells. TNF-TNFR2 signaling is known to promote CD4 + T-cell activation and proliferation. However, it is unknown if CD4 + T-cells also express TNFR1, and if elevated TNFα-TNFR1 signaling during HF mediates pathological effects of CD4 + T-cells. Using flow cytometry, we show that TNFR1 + CD4 + T-cells are amplified in the hearts at 3 days (d) and 8 weeks (wks) post-MI (HF) in mice. As compared to sham, while TNFα expression (and %) is blunted in CD4 + T-cells at 3 d post-MI, it is increased during HF with significantly higher expression in TNFR1 + T-cells as compared to TNFR1 - T-cells. Splenic CD4 + T-cells activated using anti-CD3/CD28 antibodies and treated with neutralizing anti-TNFR1 antibody showed increased T-cell proliferation, and Bcl-xL (pro-survival factor) and TNFα expression without affecting activation marker (CD69) suggesting a role of TNFR1 in mediating pro-apoptotic signaling without affecting activation. To confirm these results, we adoptively transferred (AT) HF-activated splenic WT and TNFR1 -/- T-cells (CD45.2) into CD45.1 naïve mice, and measured changes in cardiac function of recipient mice by echocardiography (as an indicator of pathological activity), and donor T-cells (as a measure of cell survival) in the blood, heart, spleen and mediastinal lymph nodes (mLNs) at 14 wks post-AT. Compared to WT, we observed amplified levels of donor TNFR1 -/- T-cells in the blood, spleen, and mLNs which were not different in the hearts. Consistently, recipient mice injected either with WT and TNFR1 -/- T-cells showed similar degrees of cardiac dysfunction. Interestingly, at 14 wks post-AT the expression of ki67, a proliferation marker, was magnified in HF-activated TNFR1 -/- T-cells (as compared to WT) infiltrated into the myocardium suggesting that TNF-TNFR1 mediates pro-survival and proliferative signaling in T-cells during HF, and not their pathogenicity. Our results also provide deeper insights into the paradoxical outcomes observed in the clinical trials antagonizing TNFα in human HF patients.
Agenesis of the lung
Authors: IS Kaya, U Dilmen
Journal: European Respiratory Journal (1989)

Agenesis of the lung is extremely rare. Developmental defects of the lung are usually associated with other congenital malformations. Half of all reported patients die either at birth or within the first 5 yrs of life. We report a case of right lung agenesis with absence of the left kidney, and fusion anomaly between ribs 4 and 5 on the left hemithorax.
Abstract P3138: The Regulatory Role Of Sirtuin 6 In Coronary Microvascular Dysfunction
Authors: Yang Wang, Molly Enrick, James Gadd, Cody Juguilon, Alyssa Clark, Liya Yin
Journal: Circulation Research (2022)

Introduction: Coronary microvascular dysfunction (CMD) is characterized by impaired endothelial-dependent vasodilation. These impairments are seen in diabetic cardiomyopathy, ischemia with no obstructive coronary artery disease, and heart failure with preserved ejection fraction (HFpEF), but detailed mechanisms have yet to be elucidated. Sirtuin 6 (Sirt6), an important member of the Sirtuin family, has been implicated in obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular diseases. Sirt6 protects EC from premature senescence, oxidative stress, and atherosclerosis by sustaining high eNOS levels and preserving cell replication. Sirt6 was reported to regulate endothelial dilation in atherosclerosis in Sirt6 heterozygous mice, but how Sirt6 regulates coronary microvascular function remains to be determined. Methods: Sirt6 knockout and wild-type (WT) mice were fed a diet high in fat and sugar (HFHS) for six months, and blood lipid and glucose were measured. Coronary arteries were isolated, and endothelial-dependent vasodilation (EDD) was assessed using myography (DMT). Echocardiography and treadmill exercise exertion tests were performed to evaluate cardiac function. Myocardial blood flow (MBF) was measured by doppler. Cardiac fibrosis was detected using trichrome staining, and molecular pathways were elucidated via gene and protein analysis. Results: Our preliminary data show that Sirt6 was downregulated in diabetes. The EDD of coronary arterioles was impaired, and the mediator of coronary vasodilation switched from NO to H 2 O 2 in the Sirt6 knockout mice. Compared to the WT mice, myocardial blood flow is decreased, ejection fraction (EF) was not changed, the running distance was reduced, and E/E’ ratio was increased in Sirt6 knockout mice. The Sirt6 targeted proteins were identified. Conclusions: Sirt6 regulated coronary microvascular function, and ablation of Sirt6 caused CMD and diastolic dysfunction. Further genetic profiling will elucidate the pathways and mechanisms converging with Sirt6 to regulate microvascular function.
Lung function development in young adults: is there a plateau phase?
Authors: DR Robbins, PL Enright, DL Sherrill
Journal: European Respiratory Journal (1995)

Numerous population studies have reported that pulmonary function following the adolescent growth phase appears to be in a steady-state, where there is little or no growth occurring up to 40 yrs of age. We examined longitudinal forced expiratory volume in one second (FEV1), changes using three different statistical approaches to determine which subjects actually have significant trends during this period. Participants, who were employees at a metal processing plant, underwent quarterly spirometry for up to 10 yrs. Test results up to 33 yrs of age were included in the analysis. Each subject's FEV1 data was first analysed using simple linear regression (SLR) to test for a statistically significant linear slope. Next, each subject's data were fitted using bootstrap sampling (BSS) of their original data, to yield reduced estimates of the slope variances and increase the power of detecting a significant trend. And thirdly, we fitted a regression breakpoint (BKPT) model to the data to find those subjects who may have piecewise linear growth or decline in function. All analyses were stratified, based on smoking status. Subjects included 111 nonsmokers and 110 smokers. Among the nonsmokers, 34 subjects had significant slopes using SLR, an additional three using BSS, and only two with BKPT. Among the smokers, 36 had a significant trend using SLR, 7 were added using BSS, and no additional subjects with BKPT. We conclude that in young adult males lung function is not in a steady-state and that as many as 40% have a significant slope, either positive or negative.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract P2117: TRF2 Rescues Pathogenic Phenotypes In Duchenne Muscular Dystrophy Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells
Authors: Asuka Eguchi, Sofia I Torres-Bigio, Adriana Fernanda G Gonzalez, Kassie Koleckar, Foster Birnbaum, Helen M Blau
Journal: Circulation Research (2022)

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Heart failure, driven by cardiomyocyte death, fibrosis, and the development of dilated cardiomyopathy, is the leading cause of death in DMD patients. Current treatments decrease the mechanical load on the heart; however, these treatments do not address the root cause of dilated cardiomyopathy: loss of cardiomyocytes. Previously, we showed that longer telomeres are protective against dilated cardiomyopathy. Here we investigated the role of telomeres as a target for therapy in DMD cardiomyocytes using human induced pluripotent stem cells (iPSCs) to model the disease. Compared to healthy controls, DMD cardiomyocytes exhibited reduced telomere lengths, cell size, nuclear size, and sarcomere density. The telomere-binding protein, TRF2, is a core component of the shelterin complex, which protects chromosome ends. TRF2 levels are reduced relative to healthy controls in DMD cardiomyocytes. We hypothesized that decreased TRF2 drives telomere attrition in the progression of dilated cardiomyopathy. Our data show that TRF2 overexpression prevented telomere attrition and also rescued deficits in cell size, nuclear size, sarcomere density, and calcium handling. These data highlight the benefits of TRF2 upregulation as a potential gene therapy to delay the onset of dilated cardiomyopathy.
Abstract EC104: Mitochondrial Microdomain Disruption Results In Sinus Node Dysfunction In Heart Failure
Authors: Lu Ren, Raghavender Reddy Gopireddy, Guy Perkins, Valeriy Timofeyev, Yankun Lyu, Daphne A Diloretto, James Overton, Wilson Xu, Nathan Grainger, Elena N Dedkova, Xiao-Dong Zhang, Ebenezer Yamoah, Manuel F Navedo, Nipavan Chiamvimonvat, Phung N Thai
Journal: Circulation Research (2022)

Introduction: Sinoatrial node (SAN), the leading pacemaker region, generates electrical impulses that propagate throughout the heart. SAN dysfunction with bradyarrhythmia is well documented in heart failure (HF). However, the underlying mechanisms are not entirely understood. Mitochondria are critical to cellular processes that determine life or death of the cell. Therefore, proper communication with the mitochondria is essential for normal cellular function. We tested the hypothesis that alterations in the mitochondria-sarcoplasmic reticulum (SR) connectomics underlie SAN dysfunction in HF. Methods: We took advantage of a mouse model of pressure-overload induced HF by transverse aortic constriction (TAC) and a SAN-specific CRISPR/Cas9 mediated gene silencing of mitofusin-2 ( Mfn2 ). Results: TAC mice exhibited impaired cardiac function with HF, cardiac fibrosis, and profound SAN dysfunction. Ultrastructural imaging using electron microscope (EM) tomography revealed abnormal mitochondrial structure with increased SR-mitochondria distance. The expression of the SR-mitochondria tether GTPase protein Mfn-2 was significantly down-regulated and showed reduced colocalization with ryanodine receptor (RyR2) in HF SAN cells. Indeed, SAN-specific gene silencing of Mfn-2 led to alterations in the mitochondrial-SR microdomains[MFN1] and SAN dysfunction. Finally, disruption in the mitochondrial-SR microdomains resulted in abnormal mitochondrial Ca 2+ handling, alterations in localized PKA activity, and impaired mitochondrial function in HF SAN cells. Conclusion: The study provides insight on the role of mitochondrial-SR microdomains in SAN automaticity and into possible therapeutic targets for SAN dysfunction in HF patients.
Abstract P2077: Caspase8ap2 M6a Mrna Methylation Enhances Cardiomyocyte Apoptosis Following Myocardial Ischemia
Authors: Roshan Kumar K Dutta, Prabhat Ranjan, qinkun zhang, Prasanna Krishnamurthy, Hind Lal, Martin E Young, Suresh Verma
Journal: Circulation Research (2022)

Objective: Heart failure is the leading cause of morbidity and mortality in the United States. Cardiomyocyte death is one of the critical mediators of cardiac dysfunction following ischemic injury. However, the role of posttranscriptional regulation on cell-death-associated genes is not well explored during ischemic heart failure. N6-methyladenosine (m6A) is the most abundant and conserved chemical modification found in eukaryotic mRNA and is associated with mRNA synthesis and metabolism. We have recently shown that m6A RNA methylation regulates the angiogenic potential of endothelial cells following ischemic injury. However, the role of m6A mRNA methylation in cardiac cell death following ischemic injury is not well defined. Methods: Cardiac function (using echocardiography) was measured at baseline and four weeks post-MI in mice. In the end, mice were euthanized, and hearts were excised for biochemical and histological analysis. Cardiac cell death was assessed in H9C2 cells and cardiomyocytes using FACs (Annexin V and PI) and TUNNEL assay. The Casp8AP2 stability were measured using actinomycin D assay. To demonstrate the molecular mechanism, METTL3 was inhibited using siRNA or shRNA. Results: The cardiac function was significantly reduced following MI. Enhanced m6A mRNA methylation was observed in mice hearts following MI. Histological (TUNEL assay) and biochemical (WB: Caspase 8, cleaved cas8, caspase3, cleaved caspase3, Casp8AP2) analysis showed increased myocytes apoptosis in mice following MI. At the molecular level, hypoxic stress (nutrient depiviation+1%O2) induces global m6A mRNA methylation, which leads to Cas8AP2 gene stability and activation of extrinsic apoptotic pathways in cardiomyocytes in vitro. In contrast, METTL3 inhibition significantly reduced Cas8AP2 mRNA methylation, enhanced its degradation, and ultimately reduced cardiomyocyte cell death. Conclusion: In conclusion, we have shown that increased Casp8AP2 m6A RNA methylation enhances its stability and activates caspase-3 cleavage, which eventually leads to cardiomyocyte death following myocardial ischemia. The reduction of the RNA methylation through METTL3 inhibition (methyltransferase) reduced hypoxia-induced apoptosis of cardiomyocytes.
Abstract P1123: Establishment Of An In Vitro Method To Evaluate Chronic Cardiac Contractility Modulation Signals In 3d Human Engineered Cardiac Tissues
Authors: TK Feaster, Jourdan Ewoldt, Maura Casciola, Akshay Narkar, Christopher S Chen, Ksenia Blinova
Journal: Circulation Research (2022)

Background: Cardiac contractility modulation (CCM) is a medical device-based therapy delivering non-excitatory electrical simulations to the heart during the absolute refractory period to enhance cardiac function. We previously evaluated the acute effects of CCM in isolated rabbit-CM and 2D hiPSC-CM monolayers, on flexible substrate, and found enhanced calcium and contractility. In the present study, we sought to extend these results to chronic studies in 3D human engineered cardiac tissues (ECTs) to develop a robust model to evaluate the long-term effects of CCM stimulation in vitro on intact human cardiac tissues. Methods: HiPSC-CMs and cardiac fibroblasts in a fibrin-based gel were combined to form ECTs (Figure 1). Morphology and contractility were evaluated. We found ECTs displayed baseline peak contraction amplitude of 194.8±80.8 a.u., (n=5) and peak force and stress of 26.5±6.8 uN, (n=5) and 87.9±22.0.8 Pa, (n=5) respectively. ECT displayed robust baseline electrophysiological (AP) properties and calcium handling properties. Chronic CCM pulses (i.e., 30 minutes) were applied using a commercial pulse generator. Under these conditions ECTs displayed enhanced contractile kinetics 29.0±0.04 %, (P&lt;0.01, n=4), relaxation kinetics 23.0±0.05 %, (P&lt;0.05, n=4), and shorter duration 32.0±0.03 %, (P&lt;0.01, n=4) relative to time matched control. Conclusion: This study provides a comprehensive characterization of chronic CCM effects on 3D ECTs. Future studies will investigate prolonged time points. These data provide an in vitro model to assess physiologically relevant mechanisms and evaluate safety and efficacy of future cardiac electrophysiology medical devices. Disclaimer: The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services.